WO1999020647A1 - Hysteromyoma remedy containing dienogest as the active ingredient - Google Patents

Hysteromyoma remedy containing dienogest as the active ingredient Download PDF

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Publication number
WO1999020647A1
WO1999020647A1 PCT/JP1998/004691 JP9804691W WO9920647A1 WO 1999020647 A1 WO1999020647 A1 WO 1999020647A1 JP 9804691 W JP9804691 W JP 9804691W WO 9920647 A1 WO9920647 A1 WO 9920647A1
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Prior art keywords
dienogest
uterine fibroids
therapeutic agent
fibroids
uterine
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PCT/JP1998/004691
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French (fr)
Japanese (ja)
Inventor
Yukio Katsuki
Minoru Shimora
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Mochida Pharmaceutical Co., Ltd.
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Publication date
Application filed by Mochida Pharmaceutical Co., Ltd. filed Critical Mochida Pharmaceutical Co., Ltd.
Priority to US09/529,640 priority Critical patent/US6274573B1/en
Priority to CA002306110A priority patent/CA2306110A1/en
Priority to JP2000516988A priority patent/JP4418102B2/en
Priority to EP98947912A priority patent/EP1029868A4/en
Priority to AU94624/98A priority patent/AU9462498A/en
Publication of WO1999020647A1 publication Critical patent/WO1999020647A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives

Definitions

  • the present invention relates to a therapeutic agent for uterine fibroids, which has few side effects such as a decrease in bone density, can be used alone or in combination with a GnRH agonist, and can be administered for a long time.
  • Dienogest is an international generic name (INN) of a known compound having a structure represented by the following formula (I) (17 «-cyanomethyl-17 ⁇ -hydroxy-estra_4, 9 (10) -dien-3-one). is there.
  • Dienogest is known to have luteinizing hormone activity, and a combination drug with ethinylestradiol is manufactured in Germany and sold as an oral contraceptive. Dienogest is also under clinical development as a therapeutic agent for endometriosis (Kohler et al., Archives Gynecol. Obstet. ), Vol. 255, pp. 594-5995, 1993), and its efficacy against endometrial cancer and breast cancer has been experimentally reported (Koki et al., Japanese Patent Application Laid-Open No. — 188026; Koki et al., Cancer, Vol. 79, pp. 169-176, 199). The effects of dienogest on fibroids have not been reported.
  • Fibroids are said to be present in 20 to 40% of women aged 30 and older, and are one of the most frequent diseases in obstetrics and gynecology.
  • Uterine fibroids differ from endometriosis and endometrial cancer in that they are benign tumors composed of smooth muscle, and uterine fibroids develop mainly in the sexual maturation phase and develop after menopause or castration. Cessation or shrinkage of the mass is observed.
  • GnRH gonadotropin-releasing hormone
  • GnRH agonists have a therapeutic effect on uterine fibroids, but also have side effects such as bone mineral loss and menopausal symptoms based on their main effect, estrogen lowering effect in blood. Highly expressed. Due to these risks, the period of taking GnRH agonist is usually restricted to about 6 months. It is also known that uterine fibroids return to their pre-treatment size when the GnRH agonist is discontinued (Freidman et al., Fertility 'and Sterility 1). .), Vol. 49, pp. 404-409, 1988).
  • luteinizing hormone has recently been shown to act as a growth-promoting factor for uterine fibroids (Rein et al., Supra; Fujii et al., Supra), and may have an adverse effect on the treatment of uterine fibroids. ing. Under these circumstances, the application of dienogest to uterine fibroids has not been excluded. Disclosure of the invention
  • GnRH agonists are currently widely used in pharmacotherapy for uterine fibroids, but the frequency of side effects such as bone resorption and climacteric symptoms is high, and the duration of administration is limited. In addition, the recoil phenomenon after taking the drug is also an important issue. Therefore, development of a therapeutic agent free of these side effects and problems is desired. Also, when used as a concomitant drug with GnRH agonist, It is also desirable to develop a drug that does not eliminate the action of gonisters to reduce fibroids, or a new drug that prevents GnRH agonists from regrowing once reduced fibroids and that reduces GnRH agonists' side effects as much as possible. It is. The present invention solves at least one of these problems.
  • dienogests were capable of meeting these requirements.
  • dienogest has the effect of reducing human uterine fibroid tissue, and, unlike GnRH agonists, has no effect on bone mineral density at all, and has a recoil phenomenon after taking medication. was significantly suppressed.
  • the dienogest which is an active ingredient of the therapeutic agent for uterine fibroids of the present invention, is a compound having the structure of the formula (I), as described above, and various pharmaceutically acceptable solvents such as water, ethanol, glycerol, and acetic acid. To form solvates.
  • a first aspect of the present invention is a therapeutic agent for uterine fibroids, comprising dienogest or a solvate thereof as an active ingredient. Further, the present invention is a therapeutic agent for uterine fibroids, which comprises, as an active ingredient, dienogest or a solvate thereof in which the recoil phenomenon after drug discontinuation is suppressed.
  • a second aspect of the present invention is the therapeutic agent for uterine fibroids for use in combination with another therapeutic agent for uterine fibroids.
  • the other therapeutic agent for uterine fibroids used in combination is a GnRH agonist, a GnRH antagonist, an aromatase inhibitor, or an antiestrogen.
  • a third aspect of the present invention is the therapeutic agent for uterine fibroids, which is intended to be administered during a drug holiday of a GnRH agonist and a GnRH antagonist.
  • the present invention also provides a method for treating uterine fibroids using dienogest or a solvate thereof, and a method for producing a therapeutic agent for uterine fibroids, comprising dienogest or a solvate thereof as an active ingredient. Also provided is the use of dienogest or a solvate thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of uterine fibroids.
  • the above-mentioned therapeutic agent of the present invention can be used for prevention of uterine fibroids and prevention of recurrence.
  • FIG. 1 shows a comprehensive statistical analysis of the effect of the test drug on human uterine fibroid tissue with respect to grafts of 14 donor samples.
  • buserelin acetate is a representative GnRH agonist and has indications for uterine fibroids.
  • MPA is the most typical luteinizing hormone preparation and can be administered orally similarly to dienogest.
  • Uterine fibroid tissue obtained by performing a total hysterectomy from a uterine fibroid patient was used. According to Aoki et al.'S method (Obstet. Gynecol., Vol. 83, pp. 220-228, 1991), the fibroid tissue was transformed into a square thigh.
  • the CB—17 skid female mice weighing 17 to 21 g were subcutaneously transplanted one by one into the back. Three weeks after the transplantation, it was confirmed that the graft had survived, and the animals were divided into groups of two per group. The first group was administered with a solvent (0.5% carboxymethylcellulose solution, hereinafter abbreviated as CMC) to serve as a control group. Dienogest and MPA were dissolved or suspended in CMC and administered orally, and buserelin acetate was administered subcutaneously for 6 weeks every day.
  • CMC carboxymethylcellulose solution
  • the volume of the uterine fibroid graft was measured using an ultrasonic diagnostic device (type SSD-650, Aloka, Tokyo) according to the method of Aoki et al.
  • the rate (%) was calculated from the following formula (A).
  • Uterine fibroid tissue obtained by performing total hysterectomy from four patients with uterine fibroids (donors) was used.
  • the animals were divided into groups. The first group received a CMC solvent to serve as a control group. Dienogest was suspended in CMC and administered orally, and buserelin acetate was administered subcutaneously for 6 consecutive days (treatment period). In each group, observation was continued for 4 weeks after the end of drug administration (follow-up period). During the experimental period, the volume of the graft was measured once a week in accordance with Experimental Example 1.
  • the volume of the graft before administration of the drug in each animal was set at 100%, and the ratio to this was calculated.
  • the average of the values obtained from two animals of the same donor and one group was expressed as the result of one case.
  • the rate of change of each graft size was measured weekly over the entire experimental period, and comprehensive analysis was performed on the grafts of the four donors.
  • the results of the analysis are shown in Fig. 1 as changes in graft volume change rate during the treatment period and the follow-up period.
  • Table 2 summarizes the graft volume change rate before and after the follow-up period for each donor. Table 2 Effect of test drug on human uterine fibroid tissue (treatment period vs. follow-up period) Drug / dose Myoma tumor volume change rate (%)
  • the effective dose of dienogest to uterine fibroid tissue shown in this experimental example was used as an oral contraceptive in Germany.
  • the dose is almost equivalent to the clinical dose of the drug (2 mg daily), and its safety has been confirmed in clinical trials (daily dose l to 4 mg) as a single agent for the treatment of endometriosis. Therefore, it seems that there is no problem.
  • MPA acts as a growth factor for uterine fibroids and is unsuitable as a therapeutic agent
  • dienogest is clearly different from conventional luteinizing hormone drugs and significantly reduces transplanted uterine fibroids. Clarified that it can be used as a therapeutic agent.
  • its efficacy is considered to exceed the effect of the existing therapeutic agent for uterine fibroids (GnRH agonist), and can be used as a new therapeutic agent for uterine fibroids.
  • dienogest Unlike GnRH agonists, dienogest usually has no effect on bone mineral density (Sasakawa et al., Japanese 'Journal' Job ', Pharmacol. Jpn. J. Pharmacol. Volume 7 (suppl.), 162p, 1995), can be a therapeutic agent for uterine fibroids with fewer side effects.
  • the recoil after discontinuation of medication which has been a problem with existing uterine fibroid treatments, has been demonstrated. It is expected to be a therapeutic agent with excellent characteristics that will be improved.
  • the therapeutic agent for uterine fibroids of the present invention is used in various aspects of hormone therapy. In other words, it may be administered alone for uterine fibroids or in combination with existing hormonal therapies provided for the treatment of uterine fibroids.
  • the combination may be simply administered to the patient at the same time as the GnRH agonist, add-back therapy, or using the GnRH agonist during the drug holiday.
  • add-back therapy the period of GnRH agonist administration alone and the period of simultaneous administration with the present therapeutic agent are combined, and the length and dose of each period are adjusted according to the patient's condition.
  • a reference by Freedman et al. Fertil. Sterility (Fertil. Steril.), Vol. 49, pp. 404-409, 1 988
  • Freedman et al. Fertil. Sterility (Fertil. Steril.)
  • Vol. 49, pp. 404-409, 1 988 can be used with reference to the MPA administration method disclosed in
  • dienogest can be used alone.
  • estrogen may be used in combination.
  • dienogest also has an action of antagonizing the bone mineral density reducing action of GnRH agonist, and when used together with GnRH agonist, enhances its main effect, but reduces side effects, and is also preferable as a concomitant drug.
  • the therapeutic agent for uterine fibroids of the present invention can be administered alone or in combination with other drugs.
  • Specific examples of the form of administration include tablets, capsules, tablets coated with sugar or skin, granules, fine granules, powders, liquid solutions or suspensions, emulsions, and fat emulsions. , Ointments, etc., used orally or parenterally, as suppositories It can be administered rectally or vaginally, subcutaneously, intramuscularly or intravenously as an injection.
  • a sustained-release preparation such as a patch, a tape, or an intradermal implant can be prepared.
  • the dosage is about 0.5 to 1 mg / day, preferably 1 to 5 mg / day, 1 to 5 times a day for adults, depending on the patient's age, weight, health condition and route of administration.
  • the dose and the number of doses can be adjusted.
  • GnRH antagonists include cetrorelix, ganirelix, lamorelix, and untide.
  • the GnRH antagonist is a therapeutic agent for uterine fibroids that exerts an estrogen inhibitory effect by directly blocking the GnRH receptor.
  • Other hormones include danazol and antiestrogens such as tamoxifen and clomiphene. Examples of aromatase inhibitors include fadrozole and vorozole.
  • Magnesium stearate 5.0 g The above ingredients are mixed, and 10 Omg each is encapsulated in a Japanese Pharmacopoeia No. 3 capsule to form a capsule.
  • the above components are appropriately mixed and formed into 150 mg tablets containing 0.40 mg of dienogest per tablet by a wet granulation compression method.
  • the above ingredients are melt-kneaded as appropriate and sealed in a package to make a suppository weighing 1.0 g per piece.
  • the therapeutic agent for uterine fibroids of the present invention can exert a therapeutic effect equal to or higher than that of a conventional hormonal therapeutic agent. For example, it can be expected to have a therapeutic effect on patients who could not be completely cured by conventional GnRH agonists. Furthermore, the therapeutic agent for uterine fibroids of the present invention is safer than conventional drugs, and can be administered for a long period of time, since the side effects that have been regarded as problems with conventional hormonal therapies (particularly GnRH agonists) do not pose any problem. can do. Specifically, there is no bone resorption or climacteric symptoms, and it is possible to continue treatment alone for at least 6 months. It can be taken for a long time until menopause to reduce fibroids.
  • it is expected as a drug that does not cause recoil during the drug holiday.
  • a GnRH agonist when used in combination with a GnRH agonist, it can be used as a drug that does not cause side effects such as bone resorption without reducing its main effect.
  • it can be administered as a highly safe drug during the drug holiday such as a GnRH agonist.

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Abstract

A hysteromyoma remedy containing dienogest or a solvate thereof as the active ingredient. It is reduced in adverse effects, suppressed in the rebound after administration, capable of being used alone or in combination with a GnRH agonist, and capable of administration and pharmaceutical preparation as peroral and percutaneous drugs and suppositories.

Description

明 ジエノゲストを有効成分とする子宮筋腫治療剤 技術分野  Akira A therapeutic agent for fibroids containing dienogest as an active ingredient
本発明は、 骨密度減少などの副作用が少なく、 単独使用、 または GnRHァゴ ニスト等との併用が可能で、 長期投与することが可能な子宮筋腫治療剤に関 する。  The present invention relates to a therapeutic agent for uterine fibroids, which has few side effects such as a decrease in bone density, can be used alone or in combination with a GnRH agonist, and can be administered for a long time.
糸田 背景技術  Itoda Background technology
ジエノゲス トは、 下記式 （ I ) で示される構造（17 «-cyanomethyl-17 β -hydroxy- estra_4， 9(10)- di en- 3- one)を有する既知化合物の国際一般名（INN) である。  Dienogest is an international generic name (INN) of a known compound having a structure represented by the following formula (I) (17 «-cyanomethyl-17β-hydroxy-estra_4, 9 (10) -dien-3-one). is there.
Figure imgf000003_0001
本化合物の性質および合成方法については、 シュバート（Schubert)等、 エルゼ ビアサイエンスパブリッシャ一ズ（Elsevier Science Publishers) 編、 ナチユラ ル ·プロダクツ ·ケミストリー 1 984 (Natural Products Chemistry 1984) 、 1 9 8 5年、 1 4 3〜1 5 8頁に概要が述べられている。
Figure imgf000003_0001
The nature and synthesis method of this compound are described in Schubert et al., Edited by Elsevier Science Publishers, edited by Natural Products Chemistry 1984, Natural Products Chemistry 1984, An outline is given on pp. 148-158, 1985.
ジエノゲストは、 黄体ホルモン活性を有することが知られており、 ドイツに於 いてェチニルエストラジオールとの合剤が製造され、 経口避妊薬として発売され ている。 ジエノゲストはまた、 子宮内膜症の治療剤としても臨床開発が進められ ており （ケ一ラ一（Kohler)ら、 アーカイブズ 'ォブ ·ギネコロジ一· アンド 'ォ ブステツ トリクス（Arch. Gynecol. Obstet. )、 第 2 5 4巻、 5 9 4〜 5 9 5頁、 1 9 9 3年） 、 また、 子宮体癌および乳癌に対する有効性が実験的に報告されて いる （甲木ら、 特開平 7— 1 8 8 0 2 6号； 甲木ら、 キヤンサ一（Cancer)、 第 7 9巻、 1 6 9〜1 7 6頁、 1 9 9 7年） 。 し力、しな力くら、 これまでのと ころ、 ジエノゲストの子宮筋腫に対する作用については報告がなされていな い。  Dienogest is known to have luteinizing hormone activity, and a combination drug with ethinylestradiol is manufactured in Germany and sold as an oral contraceptive. Dienogest is also under clinical development as a therapeutic agent for endometriosis (Kohler et al., Archives Gynecol. Obstet. ), Vol. 255, pp. 594-5995, 1993), and its efficacy against endometrial cancer and breast cancer has been experimentally reported (Koki et al., Japanese Patent Application Laid-Open No. — 188026; Koki et al., Cancer, Vol. 79, pp. 169-176, 199). The effects of dienogest on fibroids have not been reported.
子宮筋腫は 3 0歳以上の女性の 2 0〜4 0 %に存在すると言われ、 産婦人科領 域において最も発症頻度が高い疾患の一つである。 子宮筋腫は、 平滑筋により構 成された良性腫瘍である点において、 子宮内膜症や子宮体癌と異なっており、 子 宮筋腫が性成熟期を中心として発育し、 閉経や去勢の後に発育の停止あるいは腫 瘤の縮小が認められる。 そして子宮筋腫に対して、 酢酸ブセレリンに代表される ゴナドトロピン放出ホルモン （GnRH) ァゴニストを用いたホルモン療法が広 く実施されている。  Fibroids are said to be present in 20 to 40% of women aged 30 and older, and are one of the most frequent diseases in obstetrics and gynecology. Uterine fibroids differ from endometriosis and endometrial cancer in that they are benign tumors composed of smooth muscle, and uterine fibroids develop mainly in the sexual maturation phase and develop after menopause or castration. Cessation or shrinkage of the mass is observed. Hormonal therapy using gonadotropin-releasing hormone (GnRH) agonists, such as buserelin acetate, is widely used for uterine fibroids.
し力、しな力 ら、 GnRHァゴニストは、 子宮筋腫に対して治療効果を表わす半 面、 その主たる作用である血中エストロゲン低下作用に基いて、 骨塩量減少並び に更年期症状等の副作用が高頻度に発現する。 そしてこれらのリスクより、 GnRHァゴニス卜の服用期間には通常 6ヶ月程度の制限が課せられている。 また、 GnRHァゴニストの服用を中断すると、 子宮筋腫が再び治療前のサイ ズに戻ってしまう反跳現象も知られている （フリードマン （Freidman) ら、 ファーティ リティー ' アンド · ステリ リティ一 （Fertil.Steril.) 、 第 49巻、 404〜 409頁、 1 988年） 。 GnRH agonists have a therapeutic effect on uterine fibroids, but also have side effects such as bone mineral loss and menopausal symptoms based on their main effect, estrogen lowering effect in blood. Highly expressed. Due to these risks, the period of taking GnRH agonist is usually restricted to about 6 months. It is also known that uterine fibroids return to their pre-treatment size when the GnRH agonist is discontinued (Freidman et al., Fertility 'and Sterility 1). .), Vol. 49, pp. 404-409, 1988).
子宮筋腫による随判症状の改善のため古くには、 メ ドロキシプロゲステロンァ セテ一卜に代表される黄体ホルモンの使用が試みられたことがある。 しかしなが ら、 今日では単独投与における黄体ホルモンの子宮筋腫治療作用については、 疑 いがもたれている。 例えば、 子宮筋腫患者に黄体ホルモン剤を投与すると、 筋腫 細胞に核分裂像の増加が認められる （川口ら、 アメリカン ' ジャーナル 'アブ' ォブステツ トリクス · アン ド · ギネコロジ一 （Am. J. Obstet. Gynecol. ) 、 第 1 6 0巻、 6 3 7〜 6 4 1頁、 1 9 8 9年；藤井ら、 分子 ·細胞生理学、 4 6〜5 7頁、 1 9 9 7年） 。 さらに、 経口避妊薬で筋腫の増大が起こるこ とや、 血中高プロゲステロン状態である妊娠時に子宮筋腫が増大することか らも、 筋腫の増大にプロゲステロンが作用していると考えられる。  In the old days, attempts were made to use luteal hormones such as medroxyprogesterone acetate to improve uterine fibroids. However, there is now doubt about the effects of luteinizing hormone on uterine fibroids when administered alone. For example, administration of luteinizing hormone to fibroids in uterine fibroids leads to an increase in fission image in fibroid cells (Kawaguchi et al., American 'Journal' Abu 'Obsutets Trix and Ginecolod. (Am. J. Obstet. Gynecol. Fujii et al., Molecular and Cell Physiology, pp. 46-57, 199). Furthermore, it is considered that progesterone acts on fibroids because oral contraceptives increase fibroids and increase uterine fibroids during pregnancy, which is a state of high blood progesterone.
また、 先の GnRHァゴニス卜の副作用防止の目的で、 いくつかの性ホルモン 剤の併用が試みられているが、 エス トロゲン製剤は、 その直接的作用のため 危険性が心配され適当でない。 一方、 メ ドロキシプロゲステロンアセテー ト (MPA) を併用する試みでも、 ほてりや骨密度減少などの副作用は軽減される ものの、 子宮筋腫の大きさは GnRHァゴニストの単独投与時より、 肥大してし まうこと力く、 数多く報告されている。 すなわち、 黄体ホルモン剤は、 GnRHァ ゴニストの子宮筋腫の縮小作用を打ち消すとされている （フリードマンら、 前述 ；カー（Carr)ら、 ジャーナル ·ォブ · クリニカル ·ェンドクリノロジ一'メタボ リズム （J Clin Endocrinol etab. ) 、 第 7 6巻、 1 2 1 7〜 1 2 2 3頁、 1 9 9 3年； レイン（Rein)ら、 アメリカン ' ジャーナル'ォブ'ォブステツ 卜リ クス .アンド 'ギネコ口ジ一（Am. J. Obstet. Gynecol. ) 、 第 1 7 2巻、 1 4〜In addition, several sex hormonal agents have been tried in combination for the purpose of preventing the side effects of the aforementioned GnRH agonist, but estrogen preparations are not suitable because of the danger of danger due to their direct effects. On the other hand, even with attempts to use medroxyprogesterone acetate (MPA), side effects such as hot flashes and bone density reduction are reduced, but the size of uterine fibroids is larger than that of GnRH agonist alone. There are many reports. That is, luteinizing hormone drugs are thought to counteract the reducing action of GnRH agonists on uterine fibroids (Friedman et al., Supra; Carr et al., Journal of Clinical Endocrinology 1). Rhythm (J Clin Endocrinol etab.), Vol. 76, pp. 127-122, 1993; Rein et al., American 'Journal' ob 'Obstedz Trix. 'Gineko Mouth (Am. J. Obstet. Gynecol.), Vol. 17 2nd, 14-
1 8頁、 1 9 9 5年） 。 18 pages, 1995).
さらに、 抗黄体ホルモン剤である RU— 4 8 6の投与により子宮筋腫の体積が 減縮し、 治療効果が認められること （マ一フィ一 （Murphy) ら、 ジャーナル'ォ づ ' クリニカル .エンドク リノロジ一 · メタボリズム （J Clin Endocrinol Metab.：) 、 第 7 6巻、 5 1 3〜 5 1 7頁、 1 9 9 3年；イエン （Yen)ら、 U S 5 4 6 8 7 4 1号） 等が報告され、 新たに子宮筋腫の治療薬として抗黄体ホルモン 剤という考えに立った医薬品の開発も進められるに至っている （マーフィーら、 前述；ホドゲンら、 特表平 9一 5 0 8 4 1 8号） 。 これらのことから近年では、 黄体ホルモン剤は子宮筋腫に対しては増殖促進因子として働き （レイン （Rein) ら、 前述；藤井ら、 前述） 、 子宮筋腫の治療においては悪影響を及ぼすと考えら れている。 こうした状況のもと、 ジエノゲストについて子宮筋腫への適用はこれ まで省みられていなかった。 発明の開示  In addition, administration of the antiprogestin RU-486 reduced the volume of uterine fibroids and showed a therapeutic effect (Murphy et al., Journal of Clinical Endocrinology 1). · Metabolism (J Clin Endocrinol Metab. :), Vol. 76, pp. 513-517, 1993; Yen et al., US Pat. No. 5,468,741 The development of new drugs based on the idea of antiprogestins as therapeutic agents for uterine fibroids has also been promoted (Murphy et al., Supra; Hodgen et al., Tokuheihei 1991-50884-18) . Based on these facts, luteinizing hormone has recently been shown to act as a growth-promoting factor for uterine fibroids (Rein et al., Supra; Fujii et al., Supra), and may have an adverse effect on the treatment of uterine fibroids. ing. Under these circumstances, the application of dienogest to uterine fibroids has not been excluded. Disclosure of the invention
上述したように、 現在、 子宮筋腫の薬物療法に於いては、 GnRHァゴニスト が広く用いられるものの、 副作用として骨吸収作用や更年期症状などの発現頻度 が高く、 服用期間が制限されている。 また、 服用中止後の反跳現象も重要な問題 となっている。 このため、 これらの副作用や問題点のない治療剤の開発が望まれ る。 また、 GnRHァゴニストとの併用剤として用いられた場合にも GnRHァ ゴニス卜の子宮筋腫の縮小作用を消失させない薬物、 もしくは、 G n R Hァゴニ ストにより、 いったん縮小した筋腫を再度増殖させない、 そして G n R Hァゴニ ストの副作用を少しでも軽減させる新しい薬剤の開発も望まれる。 本発明は、 こ れらの課題の少なくとも 1つを解決するものである。 As described above, GnRH agonists are currently widely used in pharmacotherapy for uterine fibroids, but the frequency of side effects such as bone resorption and climacteric symptoms is high, and the duration of administration is limited. In addition, the recoil phenomenon after taking the drug is also an important issue. Therefore, development of a therapeutic agent free of these side effects and problems is desired. Also, when used as a concomitant drug with GnRH agonist, It is also desirable to develop a drug that does not eliminate the action of gonisters to reduce fibroids, or a new drug that prevents GnRH agonists from regrowing once reduced fibroids and that reduces GnRH agonists' side effects as much as possible. It is. The present invention solves at least one of these problems.
かかる状況に鑑み、 本発明者らは、 子宮筋腫に対して有効で、 同時に、 G n R Hァゴニストの副作用や問題点が少ない薬物を探索してきた。 そして、 意 外にも、 ジエノゲス卜にこれらの要求を充分に満たす能力があることを見出 した。 即ち、 ジエノゲストはヒ ト子宮筋腫組織を縮小させる作用を有し、 し 力、も、 G n R Hァゴニストと異なり、 通常骨塩量に対して影響を全く及ぼさない し、 服薬中止後の反跳現象が著明に抑制された。 これらの事に基づき鋭意研究を 行い、 本発明を完成させた。  In view of such a situation, the present inventors have searched for a drug that is effective for uterine fibroids and at the same time, has few side effects and problems of GnRH agonist. Unexpectedly, they found that dienogests were capable of meeting these requirements. In other words, dienogest has the effect of reducing human uterine fibroid tissue, and, unlike GnRH agonists, has no effect on bone mineral density at all, and has a recoil phenomenon after taking medication. Was significantly suppressed. Based on these facts, intensive research was conducted, and the present invention was completed.
本発明の子宮筋腫治療剤の有効成分となるジエノゲストは、 すでに示した 如く、 式 （I ) の構造を有する化合物であり、 水、 エタノール、 グリセロール、 酢酸等の製薬学上許容される種々の溶媒と溶媒和物を形成し得る。  The dienogest, which is an active ingredient of the therapeutic agent for uterine fibroids of the present invention, is a compound having the structure of the formula (I), as described above, and various pharmaceutically acceptable solvents such as water, ethanol, glycerol, and acetic acid. To form solvates.
本発明の第一の態様は、 ジエノゲストもしくはその溶媒和物を有効成分として 含有することを特徴とする子宮筋腫治療剤である。 また、 服薬中止後の反跳現象 が抑制されたジエノゲストもしくはその溶媒和物を有効成分として含有すること を特徴とする子宮筋腫治療剤である。  A first aspect of the present invention is a therapeutic agent for uterine fibroids, comprising dienogest or a solvate thereof as an active ingredient. Further, the present invention is a therapeutic agent for uterine fibroids, which comprises, as an active ingredient, dienogest or a solvate thereof in which the recoil phenomenon after drug discontinuation is suppressed.
本発明の第二の態様は、 他の子宮筋腫治療剤と併用するための前記子宮筋腫治 療剤である。 好ましくは、 併用される他の子宮筋腫治療剤が G n R Hァゴニ スト、 G n R Hアンタゴニスト、 ァロマターゼインヒビター、 アンチエストロゲ ンである、 子宮筋腫治療剤である。 本発明の第三の態様は、 G n R Hァゴニスト、 G n R Hアンタゴニストの休薬 期に投与されることを目的とする、 前記子宮筋腫治療剤である。 A second aspect of the present invention is the therapeutic agent for uterine fibroids for use in combination with another therapeutic agent for uterine fibroids. Preferably, the other therapeutic agent for uterine fibroids used in combination is a GnRH agonist, a GnRH antagonist, an aromatase inhibitor, or an antiestrogen. A third aspect of the present invention is the therapeutic agent for uterine fibroids, which is intended to be administered during a drug holiday of a GnRH agonist and a GnRH antagonist.
また、 本発明により併せて、 ジエノゲストまたはその溶媒和物を用いた子宮筋 腫の治療方法、 および、 ジエノゲストまたはその溶媒和物を有効成分として含有 することを特徴とする子宮筋腫治療剤の製造方法並びに、 子宮筋腫の予防、 治療 の為の医薬組成物の製造の為の、 ジエノゲストまたはその溶媒和物の使用も提供 される。  The present invention also provides a method for treating uterine fibroids using dienogest or a solvate thereof, and a method for producing a therapeutic agent for uterine fibroids, comprising dienogest or a solvate thereof as an active ingredient. Also provided is the use of dienogest or a solvate thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of uterine fibroids.
なお、 上述した本発明の治療剤は、 子宮筋腫の予防、 再発防止にも用いられう  The above-mentioned therapeutic agent of the present invention can be used for prevention of uterine fibroids and prevention of recurrence.
図面の簡単な説明 BRIEF DESCRIPTION OF THE FIGURES
図 1は、 ヒト子宮筋腫組織に及ぼす被験薬物の作用をドナ一 4検体の移植片に つ 、て総合的に統計解析したものである。 発明を実施するための最良の形態  FIG. 1 shows a comprehensive statistical analysis of the effect of the test drug on human uterine fibroid tissue with respect to grafts of 14 donor samples. BEST MODE FOR CARRYING OUT THE INVENTION
次に、 本発明の子宮筋腫治療剤の効果を、 下記の実験例によって具体的 に示す。 なお比較に用いた薬物のうち、 ブセレリ ンアセテー トは、 代表的 な G n R Hァゴニスト製剤であり、 子宮筋腫に対する適応を有している。 また、 M P Aは、 最も代表的な黄体ホルモン製剤であり、 ジエノゲスト同様経口投与が 可能である。  Next, the effects of the therapeutic agent for uterine fibroids of the present invention will be specifically shown by the following experimental examples. Of the drugs used for comparison, buserelin acetate is a representative GnRH agonist and has indications for uterine fibroids. MPA is the most typical luteinizing hormone preparation and can be administered orally similarly to dienogest.
実験例 1 ： ヒト子宮筋腫組織に対する縮小作用  Experimental Example 1: Reduction effect on human fibroid tissue
子宮筋腫の患者から子宮全摘術施行により得られた子宮筋腫組織を使用した。 ァォキ （Aoki) らの方法 （ォブステツ トリクス 'アンド 'ギネコロジー（Obstet. Gynecol. )、 第 8 3巻、 2 2 0〜 2 2 8頁、 1 9 9 4年） に従い、 筋腫組織 を 2腿四方角の小片に細切し、 体重 1 7〜2 1 gの CB— 1 7スキッ ド系雌マウ スに 1匹に 1個ずつ背部皮下移植した。 移植 3週後に、 移植片が生着したことを 確認した後、 1群 2匹ずつ群分けした。 第 1群には溶媒 （0. 5%カルボキシメ チルセルロース溶液、 以下 CMCと略す） を投与して対照群とした。 ジエノゲス ト、 MP Aは、 CMCに溶解または懸濁し経口投与にて、 ブセレリンアセテート は皮下投与にて、 6週間連日投与した。 Uterine fibroid tissue obtained by performing a total hysterectomy from a uterine fibroid patient was used. According to Aoki et al.'S method (Obstet. Gynecol., Vol. 83, pp. 220-228, 1991), the fibroid tissue was transformed into a square thigh. The CB—17 skid female mice weighing 17 to 21 g were subcutaneously transplanted one by one into the back. Three weeks after the transplantation, it was confirmed that the graft had survived, and the animals were divided into groups of two per group. The first group was administered with a solvent (0.5% carboxymethylcellulose solution, hereinafter abbreviated as CMC) to serve as a control group. Dienogest and MPA were dissolved or suspended in CMC and administered orally, and buserelin acetate was administered subcutaneously for 6 weeks every day.
6週間の薬物投与前後に Aokiらの方法に従い子宮筋腫移植片の体積を超音波診 断装置 （type SSD-650,Aloka, 東京） を用いて測定し、 各動物における子宮筋腫 移植片の体積変化率 （％) を下記の計算式 （A) より算出した。 Before and after drug administration for 6 weeks, the volume of the uterine fibroid graft was measured using an ultrasonic diagnostic device (type SSD-650, Aloka, Tokyo) according to the method of Aoki et al. The rate (%) was calculated from the following formula (A).
[X] - [Y] [X]-[Y]
体積変化率 （％) = X 1 0 0 · · · (A)  Volume change rate (%) = X 100 · · · (A)
[Y]  [Y]
[X] ：薬物投与後の体積 [Y] ：薬物投与前の体積 結果を表 1に示す。 [X]: Volume after drug administration [Y]: Volume before drug administration The results are shown in Table 1.
表 1 ヒト子宮筋腫組織に及ぼす被験薬物の作用 Table 1 Effects of test drugs on human uterine fibroid tissue
Figure imgf000010_0001
Figure imgf000010_0001
表中の数値は、 各群 2匹の平均値で示す。 表 1に示す結果より、 対照群の移植片体積が、 投与期間の前後で安定して増加 していたのに対し、 ジエノゲスト 0. 1および 1 mg/k g投与群およびブセレ リ ンアセテー ト 0. 0 3 mgZk g投与群において顕著な縮小作用が認めら れた。 用いたブセレリンァセテ一卜の投与量は、 動物において、 ゴナドトロピン を低下させるのに十分な用量であり、 臨床用量に換算した場合、 十分有効性を示 す投与量である。 驚くべきことに、 ジエノゲス卜の縮小作用はブセレリンァ セテートのそれをも上回っており、 より高い有効性を示した。 一方、 MPA投与 群においては、 移植片体積が著しく増大した。 実験例 2 ： ヒト子宮筋腫組織に対する縮小作用並びに反跳抑制作用 The numerical values in the table are shown as the average of two animals in each group. According to the results shown in Table 1, the graft volume in the control group increased steadily before and after the administration period, whereas the dienogest 0.1 and 1 mg / kg administration groups and buserelin acetate 0.0 A remarkable reduction effect was observed in the 3 mgZkg group. The dose of buserelin acetate used is a dose sufficient to reduce gonadotropin in animals, and a dose that shows sufficient efficacy when converted to a clinical dose. Surprisingly, the reducing effect of diengest was even greater than that of buserelin acetate, indicating higher efficacy. On the other hand, in the MPA group, the graft volume increased significantly. Experimental example 2: Reduction effect and recoil suppression effect on human uterine fibroid tissue
子宮筋腫の患者 （ドナー） 4名から、 子宮全摘出施行により得られた子宮筋腫 組織を使用した。 実験例 1に準じてスキッ ド系雌マウスに 2 mm四方角の筋腫組 織を皮下移植し、 移植 3週後に、 全ての移植片の生着を確認した後、 ドナ一毎に に 1群 2匹ずつ群分けした。 第 1群には CMC溶媒を投与して対照群とした。 ジ エノゲストは、 CMCに懸濁して経口投与にて、 ブセレリンアセテートは皮下投 与にて、 6週間連日投与した （治療期間） 。 何れの群についても薬物投与終了か ら引き続き 4週間観察した （フォローアップ期間） 。 実験期間中、 毎週 1回、 実 験例 1に準じて移植片体積を測定し、 各動物における薬物投与前の移植片体積を 1 0 0%として、 これに対する割合を算出した。 同一ドナ一同一群の 2匹より得 た値の平均値を 1例の結果として表わした。 実験期間全体にわたり各移植片サイ ズの変化率を毎週測定し、 ドナー 4検体の移植片について総合的に解析した。 各 群の結果を、 平均値 + Z—標準偏差 （n= 4) として表わし、 対照群に対する各 群の値の差をダネッ ト検定 （*Pく 0. 0 5, **P< 0. 0 1 ) により解析し た。 その解析結果を治療期間とフォローアップ期間での移植片体積変化率の推移 として図 1に示す。  Uterine fibroid tissue obtained by performing total hysterectomy from four patients with uterine fibroids (donors) was used. Subcutaneously transplanted a 2 mm square myoma tissue into a female skim mouse according to Experimental Example 1, and after 3 weeks from transplantation, all grafts were confirmed to have survived. The animals were divided into groups. The first group received a CMC solvent to serve as a control group. Dienogest was suspended in CMC and administered orally, and buserelin acetate was administered subcutaneously for 6 consecutive days (treatment period). In each group, observation was continued for 4 weeks after the end of drug administration (follow-up period). During the experimental period, the volume of the graft was measured once a week in accordance with Experimental Example 1. The volume of the graft before administration of the drug in each animal was set at 100%, and the ratio to this was calculated. The average of the values obtained from two animals of the same donor and one group was expressed as the result of one case. The rate of change of each graft size was measured weekly over the entire experimental period, and comprehensive analysis was performed on the grafts of the four donors. The results for each group are expressed as the mean + Z—standard deviation (n = 4), and the difference between the values of each group and the control group is Dunnett's test (* P <0.05, ** P <0.0. Analyzed by 1). The results of the analysis are shown in Fig. 1 as changes in graft volume change rate during the treatment period and the follow-up period.
また、 フォローアップ期間前後の移植片体積変化率を各ドナ一毎にまとめ、 表 2に表わす。 表 2 ヒト子宮筋腫組織におよぼす被験薬物の作用 （治療期間とフォローアップ期間の対比） 薬物/投与量 筋 腫 の 体 積 変 化 率 （％) Table 2 summarizes the graft volume change rate before and after the follow-up period for each donor. Table 2 Effect of test drug on human uterine fibroid tissue (treatment period vs. follow-up period) Drug / dose Myoma tumor volume change rate (%)
(mg/kg/曰）  (mg / kg / says)
移植片 （ドナ一 A) 移植片 （ドナ一 B) 移植片 （ドナ一 C) 移植片 （ドナ一 D) 治療後 フォロ-アップ後 治療後 フォロ-ァププ後 治療後 フォロ-アップ後 治療後 フォロ-ァ プ後 コント口一ノレ 0. 0 7. 1 + 8. 3 + 1 1. 7 0. 0 0. 0 + 1 0. 0 + 1 0. 0 Graft (Donna A) Graft (Donna B) Graft (Donna C) Graft (Donna D) After treatment After follow-up After treatment After follow-up After treatment After follow-up After treatment Follow- After uploading Control entry 0. 0 7.1 + 8. 3 + 1 1. 7 0. 0 0. 0 + 1 0. 0 + 1 0. 0
(一） ジエノゲスト - 5 7. 9 - 5 6. 2 - 4 3. 6 - 3 0. 5 - 6 8. 1 - 5 1. 2 - 4 1. 2 - 3 4. 5 (0. 1 ) ブセレリン - 4 4. 6 - 7. 7 - 3 0. 5 + 1 6. 7 - 5 6. 0 0. 0 - 2 9. 2 + 1 0. 0 (0. 1 ) (1) Dienogest-5 7. 9-5 6.2-4 3.6-3 0.5-6 8.1-5 1.2-4 1.2-34.5 (0.1) Buserelin -4 4.6-7.7-3 0.5 + 1 6.7-5 6.0.0 0.0-29.2 + 1 0.0 (0.1)
本実験において、 治療期間におけるジエノゲストの 0. lmgZkgZ日によ る子宮筋腫に対する縮小作用は、 ブセレリンの 0. l mgZk gZ日 （皮下 投与） を上回るものであった。 In this experiment, the reduction effect of dienogest on 0.1 mg mgZkgZ days of uterine fibroids during the treatment period was greater than that of buserelin on 0.1 mgZkgZ days (subcutaneous administration).
また、 フォローアップ期間の結果から、 ブセレリン投与群では、 一旦縮小した 筋腫移植片が投与終了後に再び増大する反跳現象を認めたが、 ジエノゲスト投与 群ではこのような変化が著明に抑制された。  In the follow-up period, recurrence was observed in the buserelin-treated group in which the once reduced myoma tumor graft increased again after the treatment was completed, but such a change was markedly suppressed in the dienogest-treated group. .
なお、 本発明子宮筋腫治療剤の、 毒性 （安全性） については、 本実験例におい て示されたジエノゲス卜の子宮筋腫組織に対する有効用量が、 ドイツにおいて経 口避妊薬としてすでに使用されている本薬物の臨床用量 （1日投与量 2mg) に ほぼ匹敵する用量であり、 且つ、 単剤の子宮内膜症治療薬としての臨床治験 (1日投与量 l〜4mg) においても安全性が確認されていることから、 何ら問 題ないと考えられる。  Regarding the toxicity (safety) of the therapeutic agent for uterine fibroids of the present invention, the effective dose of dienogest to uterine fibroid tissue shown in this experimental example was used as an oral contraceptive in Germany. The dose is almost equivalent to the clinical dose of the drug (2 mg daily), and its safety has been confirmed in clinical trials (daily dose l to 4 mg) as a single agent for the treatment of endometriosis. Therefore, it seems that there is no problem.
以上の実験結果より、 MP Aが子宮筋腫に対する増殖因子として働き、 治療剤 として不適切であるのに対して、 ジエノゲストは従来の黄体ホルモン剤とは明確 に異なり、 移植子宮筋腫を著しく縮小させ、 治療剤として用いられ得ることを明 確にした。 また、 その効力は、 既存の子宮筋腫治療剤 （GnRHァゴニスト） の 効果を上回ると考えられ、 新しし、子宮筋腫治療剤として用い得る。  From the above experimental results, it is clear that MPA acts as a growth factor for uterine fibroids and is unsuitable as a therapeutic agent, whereas dienogest is clearly different from conventional luteinizing hormone drugs and significantly reduces transplanted uterine fibroids. Clarified that it can be used as a therapeutic agent. In addition, its efficacy is considered to exceed the effect of the existing therapeutic agent for uterine fibroids (GnRH agonist), and can be used as a new therapeutic agent for uterine fibroids.
し力、も、 ジエノゲストは、 GnRHァゴニストと異なり、 通常骨塩量に対して 影響を全く及ぼさないため （笹川ら、 ジャパニーズ ' ジャーナル ' ォブ ' ファーマコロジ一 （Jpn. J. Pharmacol. ) 、 第 6 7巻 （suppl. ) 、 1 6 2 p, 1 995年） 、 副作用がより少ない子宮筋腫の治療剤となり得る。 更には、 ジェ ノゲストは、 既存の子宮筋腫治療剤で問題とされている投薬中止後の反跳現象が 改善されるという、 優れた特徴を有する治療剤となるものと期待される。 Unlike GnRH agonists, dienogest usually has no effect on bone mineral density (Sasakawa et al., Japanese 'Journal' Job ', Pharmacol. Jpn. J. Pharmacol. Volume 7 (suppl.), 162p, 1995), can be a therapeutic agent for uterine fibroids with fewer side effects. In addition, Genogest noted that the recoil after discontinuation of medication, which has been a problem with existing uterine fibroid treatments, has been demonstrated. It is expected to be a therapeutic agent with excellent characteristics that will be improved.
本発明の子宮筋腫治療剤は、 ホルモン療法の種々の態様で用いられる。 すなわ ち、 子宮筋腫に対して単独で投与される他、 子宮筋腫治療の目的で供される既存 のホルモン療法剤と組み合わせた投与方法が考えられる。 併用の方法としては、 患者に対して単純に G n RHァゴニストと同時に投与される他、 add- back療 法や、 GnRHァゴニストの休薬期間中の使用などがあり得る。 add- back療法で は、 GnRHァゴニスト単独投与期間と本治療剤との同時投与期間とが組み合わ され、 各期間の長さや投与量は、 患者の態様に応じて調整される。 具体例として は、 フ リー ドマンらの文献 （フ リー ドマン （Freidman) ら、 ファーティ リ ティ一 ' アン ド ' ステリ リティー （Fertil. Steril. ) 、 第 4 9巻、 4 0 4〜 409頁、 1 988年） に開示される MP Aの投与方法を参考に本剤が使用され 得る。  The therapeutic agent for uterine fibroids of the present invention is used in various aspects of hormone therapy. In other words, it may be administered alone for uterine fibroids or in combination with existing hormonal therapies provided for the treatment of uterine fibroids. The combination may be simply administered to the patient at the same time as the GnRH agonist, add-back therapy, or using the GnRH agonist during the drug holiday. In add-back therapy, the period of GnRH agonist administration alone and the period of simultaneous administration with the present therapeutic agent are combined, and the length and dose of each period are adjusted according to the patient's condition. As a specific example, a reference by Freedman et al. (Freidman et al., Fertil. Sterility (Fertil. Steril.), Vol. 49, pp. 404-409, 1 988) can be used with reference to the MPA administration method disclosed in US Pat.
本 add- back療法において、 ジエノゲストは単独で用いられ得る。 また、 更にェ ストロゲンも併用し得る。  In this add-back therapy, dienogest can be used alone. In addition, estrogen may be used in combination.
また、 ジエノゲストは、 GnRHァゴニストの骨塩量減少作用に拮抗する作用 をも有しており、 GnRHァゴニストと併用してもその主作用を増強する一方、 副作用は軽減し、 併用剤としても好ましい。  Further, dienogest also has an action of antagonizing the bone mineral density reducing action of GnRH agonist, and when used together with GnRH agonist, enhances its main effect, but reduces side effects, and is also preferable as a concomitant drug.
次に本発明の子宮筋腫治療剤の投与形態について述べる。 本発明の子宮筋腫治 療剤は、 単独で投与するか、 もしくは他の薬物と併用することが可能である。 投 与の形態としての具体例は、 例えば錠剤、 カプセル剤、 糖または剤皮で被膜され た錠剤、 顆粒剤、 細粒剤、 散剤、 液体状の溶液または懸濁剤、 乳濁剤、 脂肪 乳剤、 軟膏剤等の形態で、 経口的あるいは非経口的に用いられる他、 坐剤として 直腸内または膣内に、 注射剤として皮下、 筋肉内、 静脈内に投与されうる。 また、 パッチ剤、 テープ剤、 皮内埋め込み型等の徐放性製剤とすることもで きる。 Next, the administration form of the therapeutic agent for uterine fibroids of the present invention will be described. The therapeutic agent for uterine fibroids of the present invention can be administered alone or in combination with other drugs. Specific examples of the form of administration include tablets, capsules, tablets coated with sugar or skin, granules, fine granules, powders, liquid solutions or suspensions, emulsions, and fat emulsions. , Ointments, etc., used orally or parenterally, as suppositories It can be administered rectally or vaginally, subcutaneously, intramuscularly or intravenously as an injection. In addition, a sustained-release preparation such as a patch, a tape, or an intradermal implant can be prepared.
投与量は、 成人一日当り、 約 0. 5〜1 Omg、 好ましくは 1〜5mgで一日 当り 1〜5回に分けて投与されるが、 患者の年齢、 体重、 健康状態および投与経 路により、 投与量、 投与回数ともに調節できる。  The dosage is about 0.5 to 1 mg / day, preferably 1 to 5 mg / day, 1 to 5 times a day for adults, depending on the patient's age, weight, health condition and route of administration. The dose and the number of doses can be adjusted.
本発明の子宮筋腫治療剤と併用される薬物の具体的な例は、 G n R Hァゴニス トとしてはブセレリン、 リュープロレイン、 ゴセレリン、 ナファレリン、 トリプ トレリン、 デスロレリン、 ァボレリン等がある。 GnRHアンタゴニストとして は、 セトロレリクス、 ガニレリクス、 ラモレリクス、 アンタイ ド等があげら れる。 ここで、 GnRHアン夕ゴニストは、 直接 GnRHレセプタ一をブロック してエストロゲン抑制作用を発揮する子宮筋腫の治療剤である。 その他のホルモ ン剤としてダナゾ一ル、 アンチエストロゲンとして、 タモキシフェン、 クロ ミフヱンなどがある。 ァロマターゼインヒビタ一としては、 フア ドロゾール、 ボ ロゾール等がある。  Specific examples of the drug used in combination with the therapeutic agent for uterine fibroids of the present invention include buserelin, leuprolein, goserelin, nafarelin, triptorelin, deslorelin, and aborelin as GnRH agonists. GnRH antagonists include cetrorelix, ganirelix, lamorelix, and untide. Here, the GnRH antagonist is a therapeutic agent for uterine fibroids that exerts an estrogen inhibitory effect by directly blocking the GnRH receptor. Other hormones include danazol and antiestrogens such as tamoxifen and clomiphene. Examples of aromatase inhibitors include fadrozole and vorozole.
以下に、 本発明の実施例を示す。 なお、 本発明は、 以下の実施例に何ら限定さ れるものではない。  Hereinafter, examples of the present invention will be described. It should be noted that the present invention is not limited to the following examples.
(実施例 1 )  (Example 1)
ジエノゲスト 2. 0 g  Dienogest 2.0 g
乳糖 8 7. 0 g  Lactose 8 7.0 g
コーンスターチ 6. 0 g  Corn starch 6.0 g
ステアリン酸マグネシゥム 5. 0 g 上記成分を混合し、 1 0 Omgずつを日本薬局方 3号カプセルに封入し、 カブ セル剤となす。 Magnesium stearate 5.0 g The above ingredients are mixed, and 10 Omg each is encapsulated in a Japanese Pharmacopoeia No. 3 capsule to form a capsule.
(実施例 2 )  (Example 2)
ジエノゲスト 0. 4 g  Dienogest 0.4 g
乳糖 9 1. 6 g  Lactose 9 1.6 g
コーンスターチ 5 0. 0 g  Corn starch 50.0 g
タルク 3. 0 g  Talc 3.0 g
ステアリ ン酸マグネシウム 5. 0 g  Magnesium stearate 5.0 g
上記成分を適宜混合し、 湿式顆粒圧縮法により 1錠当りジエノゲスト 0. 4 0 mgを含有する 1 5 0 m gの錠剤となす。  The above components are appropriately mixed and formed into 150 mg tablets containing 0.40 mg of dienogest per tablet by a wet granulation compression method.
(実施例 3 )  (Example 3)
ジエノゲスト 1. 5 g  Dienogest 1.5 g
ポリオキシエチレンラウリルエーテル 3 8. 5 g  Polyoxyethylene lauryl ether 38.5 g
グリセリン 2 0. 0 g  Glycerin 20.0 g
上記成分を適宜溶融練合し、 パッケージに封入して、 1個当り重量 1. 0 gの 坐剤となす。  The above ingredients are melt-kneaded as appropriate and sealed in a package to make a suppository weighing 1.0 g per piece.
(実施例 4 )  (Example 4)
ジエノゲスト 1. 0 g  Dienogest 1.0 g
ポリソルべ一ト 8 0 1. 0 g  Polysorbate 8 0 1.0 g
ウイテツプゾ一ル （S— 5 5) 9 8. 0 g  Witepsol (S-55) 9 8.0 g
上記成分を加温下練合し、 プラスチックパッケージに封入して、 1個当り重 1. 0 gの坐剤となす。 産業上の利用可能性 The above ingredients are kneaded under heating and sealed in a plastic package to make a suppository weighing 1.0 g per piece. Industrial applicability
本発明の子宮筋腫治療剤により、 従来のホルモン療法剤と同等以上の治療効果 を発揮し得る。 例えば、 従来の G n R Hァゴニストでは治癒しきれなかった患者 に対する治療効果をも期待し得る。 さらに、 本発明の子宮筋腫治療剤では、 従来 のホルモン療法剤 （特に G n R Hァゴニス卜） で問題視された副作用が全く問題 にならないため、 従来薬に比して安全で、 しかも長期間投与することができる。 具体的には、 骨吸収作用や更年期症状などの発現がなく、 単独で 6ヶ月以上投与 を継続することが可能である。 また、 閉経までの長期にわたり服用し、 筋腫を縮 退させることができる。 或いは休薬期の反跳現象が起こらない薬物として期待さ れる。 また、 G n R Hァゴニスト等との併用においても、 その主作用を減じるこ となく、 骨吸収などの副作用をきたさない薬物として用い得る。 また、 G n R H ァゴニスト等の休薬期に安全性の高い薬物として投与され得る。  The therapeutic agent for uterine fibroids of the present invention can exert a therapeutic effect equal to or higher than that of a conventional hormonal therapeutic agent. For example, it can be expected to have a therapeutic effect on patients who could not be completely cured by conventional GnRH agonists. Furthermore, the therapeutic agent for uterine fibroids of the present invention is safer than conventional drugs, and can be administered for a long period of time, since the side effects that have been regarded as problems with conventional hormonal therapies (particularly GnRH agonists) do not pose any problem. can do. Specifically, there is no bone resorption or climacteric symptoms, and it is possible to continue treatment alone for at least 6 months. It can be taken for a long time until menopause to reduce fibroids. Alternatively, it is expected as a drug that does not cause recoil during the drug holiday. Also, when used in combination with a GnRH agonist, it can be used as a drug that does not cause side effects such as bone resorption without reducing its main effect. In addition, it can be administered as a highly safe drug during the drug holiday such as a GnRH agonist.

Claims

請求の範囲 The scope of the claims
1 . ジエノゲストまたはその溶媒和物を有効成分として含有することを特徴と する子宮筋腫治療剤。 1. An agent for treating uterine fibroids, comprising dienogest or a solvate thereof as an active ingredient.
PCT/JP1998/004691 1997-10-17 1998-10-16 Hysteromyoma remedy containing dienogest as the active ingredient WO1999020647A1 (en)

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US09/529,640 US6274573B1 (en) 1997-10-17 1998-10-16 Method of treatment for uterine leiomyoma
CA002306110A CA2306110A1 (en) 1997-10-17 1998-10-16 Therapeutic agent of uterine leiomyoma, containing dienogest as effective ingredient
JP2000516988A JP4418102B2 (en) 1997-10-17 1998-10-16 Treatment for uterine fibroids containing dienogest as an active ingredient
EP98947912A EP1029868A4 (en) 1997-10-17 1998-10-16 Hysteromyoma remedy containing dienogest as the active ingredient
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